Abnormal cell proliferation is usually characterized by an increased rate of division and in some cases uncontrolled growth. One example of a proliferative cell disorder is a tumor. In addition to posing a serious health risk in and of themselves, primary malignant tumors are particularly problematic given their tendency to invade surrounding tissues and metastasize to distant organs in the body. To date, the most frequently used methods for treating neoplasia, especially solid tumor forms of neoplasia, include surgical procedures, radiation therapy, drug therapies, and combinations of the foregoing.
Drug therapy for breast cancer may include the administration of exemestane to a patient. Product information available on-line from the U.S. Food and Drug Administration describes exemestane as an irreversible, steroidal aromatase inactivator. Exemestane (which is sold under the AROMASIN® trademark), is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structural formula is as follows:
Among other things, exemestane lowers circulating estrogen concentrations in postmenopausal women thereby providing a treatment for some postmenopausal patients with hormone-dependent breast cancer.
U.S. Pat. Nos. 4,808,616, and 4,904,650 describe 6-alkylidenandrosta-1,4-diene-3,17-dione derivatives, such as exemestane, and methods of making them. U.S. Pat. No. 4,876,045 teaches a method of preparing 6-methylene derivatives of androsta-1,4-diene-3,17-diones by reacting a 17-hydroxy precursor with formaldehyde and an amine, and then oxidizing the resulting compound. U.S. Pat. No. 4,990,635 teaches a process for making 6-methylene derivatives of androsta-1,4-diene-3,17-diones by reacting androsta-3,5-diene-17-one with formaldehyde and an amine, and then dehydrogenating the resulting compound.
The preparation of intermediates that may be useful in preparing exemestane is also described in the literature. In U.S. Pat. No. 3,274,176, there is described a process for making 1,3-dipyrrolidyl-Δ3,5-androstadiene-17-one in which Δ1,4-androstadiene-3,17-dione is refluxed with pyrrolidine and the residue is crystallized in methanol to obtain 1,3-dipyrrolidyl-Δ3,5-androstadiene-17-one. In German patent DD 258820, 6-hydroxymethyl-androsta-1,4-diene-3,17-dione is prepared from androsta-1,4-diene-3,17-dione via 1,3-dipyrrolidinoandrosta-3,5-dien-17-one. A solution of 1,3-dipyrrolidinoandrosta-3,5-dien-17-one in benzene-ethanol is stirred with aqueous formaldehyde (HCHO) until the reaction is complete. Co-pending international application no. PCT/US2005/001248 filed Jan. 14, 2005 (PCT Publication Number WO 2005/070951) also describes the preparation of intermediates that are useful in preparing exemestane, such application as is incorporated herein by reference, in its entirety.
The clinical pharmacology in this exemestane product information states that the mechanism of action for breast cancer cell growth may be estrogen-dependent. Aromatase is described as the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. It is reported that the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatese enzyme. Estrogen deprivation through aromatase inhibition is described as an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer. Exemestane as an irreversible, steroidal aromatase inactivator is believed to act as a false substrate for the aromatase enzyme, and processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation. Exemestane lowers circulating estrogen concentrations in postmenopausal women thereby providing a treatment for some postmenopausal patients with hormone-dependent breast cancer.
However, a need still exists to identify new and effective agents for treating cancer.